HIV-1 associated neurologic disease is believed to be the result of a chronic inflammatory state, in which soluble neurotoxic molecules, of both viral and cellular origin, act to cause neuronal injury and dysfunction. We hypothesize that HIV-1 neurotoxicity is opposed by a number of endogenous pathways and mediators, which serve to protect neurons. For example, neurotrophins can augment neuronal survival and function through the activation of specific receptors (Trk receptors) and subsequent initiation of signaling cascades. We therefore propose to study endogenous neuroprotective pathways that may provide us with new therapeutic strategies for neuroAIDS. This will be achieved through two specific aims. In Aim 1, experiments will focus on signaling pathways associated with neurotrophin receptor activation, including analyses of the neuroprotective effects of inhibitors of mixed lineage kinases (MLK)-3, p38 kinase and c-Jun NH2 terminal kinases (JNK), as well as peptidomimetic Trk ligands. Effects on the survival and function of neurons exposed to candidate HIV-1 neurotoxins will be evaluated, as will effects on monocyte/microglial activation. In the second aim, we will evaluate the cell signaling events that are modulated in response to the inhibition of MLK-3, using both pharmacological and genetic approaches. These experiments will take advantage of available dominant negative mutants and MLK-3 knockout mice (to genetically target MLK-3), as well as extant pharmacologic compounds and new, highly specific MLK-3 blockers that will be developed by our commercial partner. Collectively, these investigations will identify novel neuroprotective strategies that may enhance neuronal function and survival in neuroAIDS. Results from these studies will be correlated with intracellular signaling events that occur in response to drug treatment, in order to identify new therapeutic targets..